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J Mol Biol. 2007 Oct 5;372(5):1189-203. Epub 2007 Apr 27.

Conformational dynamics of the molecular chaperone Hsp90 in complexes with a co-chaperone and anticancer drugs.

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Cambridge University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK; Department of Biochemistry, University of Cambridge, Old Addenbrookes Site, 80 Tennis Court Road, Cambridge, CB2 1GA, UK.


The molecular chaperone Hsp90 is essential for the correct folding, maturation and activation of a diverse array of client proteins, including several key constituents of oncogenic processes. Hsp90 has become a focus of cancer research, since it represents a target for direct prophylaxis against multistep malignancy. Hydrogen-exchange mass spectrometry was used to study the structural and conformational changes undergone by full-length human Hsp90beta in solution upon binding of the kinase-specific co-chaperone Cdc37 and two Hsp90 ATPase inhibitors: Radicicol and the first-generation anticancer drug DMAG. Changes in hydrogen exchange pattern in the complexes in regions of Hsp90 remote to the ligand-binding site were observed indicating long-range effects. In particular, the interface between the N-terminal domain and middle domains exhibited significant differences between the apo and complexed forms. For the inhibitors, differences in the interface between the middle domain and the C-terminal domain were also observed. These data provide important insight into the structure of the biologically active form of the protein.

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